Transgenerational reproductive risks of BPA: epigenetic mechanisms and biomarker applications. A critical review.

Bisphenol A (BPA), which is a common ingredient of plastics and epoxy resins, is among the most commonly found endocrine-disrupting chemicals in the human environment. Chronic human exposure has raised concerns over its effects on reproductive health. There is growing evidence showing that BPA causes epigenetic changes, primarily DNA methylation, histone changes, and non-coding RNA changes that result in hormonal imbalances, a disruption in gametogenesis, and fertility impairment. This review summarizes current understanding of how BPA alters male reproductive performance in exposed individuals, including impaired spermatogenesis and sperm quality, endocrine imbalance, and disruption of hypothalamic-pituitary-gonadal (HPG) signaling, often in concert with oxidative stress and altered steroidogenesis. We then discuss evidence that BPA exposure, especially during critical developmental windows, can reprogram the paternal germline, such that epigenetic alterations carried by sperm, such as DNA methylation changes, abnormal histone acetylation (H3K9ac, H3K27ac, H4K12ac), disrupted histone-to-protamine transition, and altered sperm small RNAs/miRNA profiles, can contribute to fertility defects in subsequent generations. Moreover, various therapeutic methods, like epigenetic drugs and natural products such as resveratrol, naringenin, and genistein, are being studied to reverse or alleviate the impact of BPA. Given BPA's ubiquity, these findings also highlight the necessity of stricter regulation, health education to the general population, along with research into potential safer alternatives. Learning the ways BPA is remodeling the epigenome and fertility through generations is essential to protecting reproductive health and the basis of policy intervention.